2Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada

3Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada

Corresponding author: Dennis E. Vance, dennis.vance{at}ualberta.ca.

Abstract

Phosphatidylethanolamine (PE) N-methyltransferase (PEMT) catalyzes the synthesis of phosphatidylcholine (PC) in the liver. Mice lacking PEMT are protected
against diet-induced obesity and insulin resistance. We investigated the role of PEMT in hepatic carbohydrate metabolism in
chow-fed mice. A pyruvate tolerance test revealed that PEMT deficiency greatly attenuated gluconeogenesis. The reduction in
glucose production was specific for pyruvate; glucose production from glycerol was unaffected. Mitochondrial PC levels were
lower and PE levels were higher in livers from Pemt−/− compared with Pemt+/+ mice, resulting in a 33% reduction of the PC-to-PE ratio. Mitochondria from Pemt−/− mice were also smaller and more elongated. Activities of cytochrome c oxidase and succinate reductase were increased in mitochondria
of Pemt−/− mice. Accordingly, ATP levels in hepatocytes from Pemt−/− mice were double that in Pemt+/+ hepatocytes. We observed a strong correlation between mitochondrial PC-to-PE ratio and cellular ATP levels in hepatoma cells
that expressed various amounts of PEMT. Moreover, mitochondrial respiration was increased in cells lacking PEMT. In the absence
of PEMT, changes in mitochondrial phospholipids caused a shift of pyruvate toward decarboxylation and energy production away
from the carboxylation pathway that leads to glucose production.